Interleukin-6 expression was regulated by epigenetic mechanisms in response to influenza virus infection or dsRNA treatment

Interleukin-6 (IL-6) is a multifunctional cytokine that plays critical roles in a wide range of biologic activities. However, it remains unknown whether epigenetic mechanisms are involved in these processes. The possible epigenetic mechanisms involved in IL-6 expression during influenza virus (IV) infection were investigated in this study. Our results showed that both IV and its replicative intermediate dsRNA activated the IL-6 promoter, increased its transcription and enhanced cytokine secretion. IL-6 was up-regulated by DNA methyltransferase inhibitor 5-aza-2′-deoxycytidine (DAC) treatment, while its promoter activity was decreased when promoter DNA was methylated in vitro. Further study found that the IL-6 proximal promoter region was demethylated after both IV infection and dsRNA treatment, subsequently impairing its binding by transcription factors. Moreover, the DNA methyltransferase (DNMT) activity was inhibited in dsRNA treated nuclei, and DNMT1 but not DNMT3a or DNMT3b was responsible for IL-6 expression in this process. These results implied that IL-6 expression was regulated by promoter demethylation induced by down-regulation of DNMT activity. Our work revealed that epigenetic mechanisms regulate host genes expression in IV infection, and provided a new insight into understanding the mechanisms of viral infection.